Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

J Exp Med. 2019 Apr 1;216(4):757-771. doi: 10.1084/jem.20181812. Epub 2019 Feb 25.


Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,6'-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,6'-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Membrane
  • Escherichia coli / metabolism
  • Feces / microbiology
  • Humans
  • Lectins, C-Type / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mycobacterium / metabolism*
  • Phospholipids / metabolism*
  • Phylogeny
  • Receptors, Immunologic / metabolism
  • Salmonella typhi / metabolism*
  • Transferases (Other Substituted Phosphate Groups) / metabolism
  • Trehalose / metabolism*
  • Typhoid Fever / metabolism
  • Typhoid Fever / microbiology


  • CLEC4D protein, human
  • Clecsf8 protein, mouse
  • Lectins, C-Type
  • Membrane Proteins
  • Phospholipids
  • Receptors, Immunologic
  • Trehalose
  • Transferases (Other Substituted Phosphate Groups)
  • cardiolipin synthetase